Autophagy consists of the sequestration of organelles and proteins in autophagic vesicles (AV) and degradation of this cargo through lysosomal fusion (1). Autophagy allows tumor cells to survive metabolic and therapeutic stresses (2-5). Multiple publications indicate therapy-induced autophagy is a key resistance mechanism to many anti-cancer agents. Chloroquine (CQ) (Compound 1, FIG. 1) derivatives block autophagy by inhibiting the lysosome (3, 6, 7). A randomized phase III trial of CQ versus placebo with carmustine and radiation in patients with glioma reported a trend towards a doubling in duration of survival in the patients treated with CQ (8). Based on these findings, clinical trials combining cancer therapies with hydroxychloroquine (HCQ; FIG. 1 Compound 2), (which is safer than CQ to dose escalate) have been launched. Preliminary results indicate these combinations have activity (9), but it is still unclear if this activity is consistently due to the addition of HCQ. High micromolar concentrations of HCQ are required to inhibit autophagy. While there is some pharmacodynamic evidence of autophagy inhibition with HCQ in cancer patients, it is inconsistent because adequate concentrations are not achieved in all patients (10). There is an unmet need to develop more potent inhibitors of autophagy. The design and synthesis of dimeric analogs of CQ, that exploit the thermodynamic advantages imparted by polyvalency (11, 12), has been a subject of intensive study for over 10 years (13-15). An early report by Vennerstrom (14) described the synthesis of heteroalkane-bridged bisquinolines as potential antimalarials, but none of the compounds had sufficient antimalarial activity to warrant further investigation. Subsequently, Sergheraert (13) reported that tetraquinolines, i.e., dimers of bisquinolines, afforded potent antimalarials, confirming the possibility that the application of the polyvalency strategy could afford increased potency, at least with respect to antimalarial activity.
More recently, Lee (16) has described the potentiation of AKT inhibitors by fluorinated quinoline analogs. Solomon (17) has reported the preparation of “repositioned” chloroquine dimers, based on the use of a piperazine connector. These results suggest that these chloroquine analogs could serve as bases for the development of a new group of effective cancer chemotherapeutics.